1. Field of the Invention
The present invention relates generally to the fields of developmental biology and molecular biology. More particularly, it concerns gene regulation and cellular physiology in cardiomyocytes and skeletal muscle cells. Specifically, the invention relates to the inhibition of an miRNA that results in reduced expression of β-myosin heavy chain (β-MHC), thereby treating cardiac hypertrophy and heart failure. Also contemplated is up-regulation of this miRNA to treat musculoskeletal diseases.
2. Description of Related Art
Cardiac hypertrophy in response to an increased workload imposed on the heart is a fundamental adaptive mechanism. It is a specialized process reflecting a quantitative increase in cell size and mass (rather than cell number) as the result of any, or a combination of, neural, endocrine or mechanical stimuli. Hypertension, another factor involved in cardiac hypertrophy, is a frequent precursor of congestive heart failure. When heart failure occurs, the left ventricle usually is hypertrophied and dilated and indices of systolic function, such as ejection fraction, are reduced. Clearly, the cardiac hypertrophic response is a complex syndrome and the elucidation of the pathways leading to cardiac hypertrophy will be beneficial in the treatment of heart disease resulting from various stimuli.
Pathological myocardial hypertrophy is characterized by an increase in cardiomyocyte protein and the expression of a gene profile reminiscent of early embryonic development. Specifically, expression of β-myosin heavy chain (β-MHC), skeletal α-actin (sACT), and both atrial and brain natriuretic peptides (ANP and BNP, respectively) increases, whereas that of the adult cardiac muscle-specific genes, α-myosin heavy chain (α-MHC) and sarcoplasmic reticulum Ca2+-ATPase (SERCA), decreases. In particular, there is compelling evidence indicating a role for changes in MHC isoform expression in the pathogenesis of heart failure in humans. Indeed, α-MHC mRNA and protein levels are markedly reduced in failing human hearts, and improvement of left-ventricular ejection fraction through beta-blocker therapy is associated with normalization of α-MHC expression. Additionally, a mutation in the human α-MHC gene was identified in association with hypertrophic cardiomyopathy, which demonstrates that, despite its low abundance, the level of α-MHC expression is critical for normal heart function. Thus, it is clear that both α- and β-MHC play a role in the development of cardiac hypertrophy, but the precise features by which these products act in creating and/or maintaining the pathologic state remain unknown.